Selective Irreversible Inhibitors of the Wnt-Deacylating Enzyme NOTUM Developed by Activity-Based Protein Profiling

By Radu M. Suciu, Armand B. Cognetta Jr., Zachary E. Potter, B. Cravatt. 2018

44 citations recorded by the source corpus.

Wnt proteins are secreted morphogens that play critical roles in embryonic development and tissue remodeling in adult organisms. Aberrant Wnt signaling contributes to diseases such as cancer. Wnts are modified by an unusual O-fatty acylation event (O-linked palmitoleoylation of a conserved serine) that is required for binding to Frizzled receptors. O-Palmitoleoylation of Wnts is introduced by the porcupine (PORCN) acyltransferase and removed by the serine hydrolase NOTUM. PORCN inhibitors are under development for oncology, while NOTUM inhibitors have potential for treating degenerative diseases. Here, we describe the use of activity-based protein profiling (ABPP) to discover and advance a class of N-hydroxyhydantoin (NHH) carbamates that potently and selectively inhibit NOTUM. An optimized NHH carbamate inhibitor, ABC99, preserves Wnt-mediated cell signaling in the presence of NOTUM and was also converted into an ABPP probe for visualizing NOTUM in native biological systems.

Subfields: Molecular Biology, Oncology

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In Molecular Biology

Paul V. Fish

Citations in the corpus

Designed switch from covalent to non-covalent inhibitors of carboxylesterase Notum activity (2023, background): “Building on N -acyl indoline 3a , a range of N -acyl scaffolds 3b - 3o were sourced and screened ( [10] and butyric ester 2a [22] inactivate Notum through acylation of Ser232.”
Single-Cell Profiling and SCOPE-Seq Reveal Lineage Dynamics of Adult Ventricular-Subventricular Zone Neurogenesis and NOTUM as a Key Regulator (2020, unknown): “We modulated NOTUM activity in the V-SVZ using either a selective small molecule inhibitor (ABC99) (Suciu et al., 2018) or a recombinant mouse NOTUM protein.”